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Analysis of Multiple Factors Influencing ADC Pharmacokinetics

Antibody-drug conjugates (ADCs) are complex molecules wherein monoclonal antibodies are linked to cytotoxic drugs (small molecule payloads) via ADC linkers to form conjugates. In 2000, the US FDA approved the first ADC ( You may be interested in reading: Antibody-drug conjugates ADCs list Approved by FDA 2000-2023), Gemtuzumab ozogamicin (Mylotarg), for the treatment of CD33-positive acute myeloid leukemia. Due to adverse events, particularly hepatic toxicity, Mylotarg was withdrawn from the market in 2010 and subsequently re-approved in 2017. Since the approval of Mylotarg in 2000, pharmaceutical companies have been highly focused on ADC development.

ADC combines the selectivity of antibodies with the efficacy of small molecule drugs, thereby enabling more precise and targeted therapeutic applications. ADCs consist of three components: monoclonal antibodies, payloads, and linkers. All three components are crucial in designing ADCs. In modern drug development, pharmacokinetics (PK) plays a significant role in designing safe and effective doses for treating diseases.

Several factors can alter the PK of drugs, including both “intrinsic” and “extrinsic” factors. For small molecules, the influence of both internal and external factors has been well established. It is widely known that age, gender, disease status (such as renal and hepatic impairment), and drug-drug interactions affect the PK of small molecules.

However, for large molecules, the impact of these factors has not been well established. Since ADCs are combination products of monoclonal antibodies conjugated with small molecules, both intrinsic and extrinsic factors may influence the small molecules and monoclonal antibodies of ADCs.

Intrinsic Factors Influencing ADC Pharmacokinetics

Internal factors are those that are related to the individual. For example, age, gender, genetics, and disease status are all internal factors.

External factors, on the other hand, are influences from outside. For example, drug-drug interactions, food or beverage consumption, smoking, nutritional deficiencies, and other environmental factors.

Based on ten FDA-approved ADCs, the overall conclusion regarding age differences between older and younger populations is that there is insufficient data to determine PK differences between these two age groups. Population pharmacokinetics (POPPK) could not detect PK differences, and there were no clinically meaningful PK differences between the two age groups.

Gender and Race
Gender has no clinical impact on PK, as POPPK could not detect PK differences or no available information exists. The EMA stated, “Adult population models show no significant effect of race on Mylotarg PK.” Additionally, it should be noted that the sample size based on race is insufficient to determine the influence of race on Mylotarg PK in POPPK studies.

For all ten ADCs, the FDA drug labels did not provide any PK information regarding pediatrics. To date, only two ADCs have undergone PK studies in pediatrics.

Buckwalter et al. studied the PK of Mylotarg in pediatric patients with relapsed or refractory AML. The validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the antibody portion and small molecule payload in plasma samples. Children aged 1 to 16 years received a dose of 9 mg/m2. There were two infants (0-2 years old), five children (3-11 years old), and seven adolescents (12-16 years old).

PK parameters were assessed via non-compartmental analysis: infants, children, and adolescents had clearance rates of 30 mL/h, 60 mL/h, and 260 mL/h for Mylotarg, respectively, while adults had a clearance rate of 270 mL/h. The steady-state volume of distribution (Vss) for infants, children, and adolescents was 2.9 L, 3.9 L, and 9.4 L, respectively, compared to 20 L for adults. Although the sample size was small, the study indicated that PK of Mylotarg varies with age in the pediatric population.
Additionally, Flerlage et al. conducted a POPPK study of Adcetris in 16 pediatric patients with Hodgkin lymphoma (6-18 years old). Compared to adults, pediatric Adcetris had 25% lower AUC and 11% lower Cmax. The greatest impact of age on drug PK typically occurs in younger age groups (≤5 years old).

Renal Impairment
The payload of ADCs is typically small molecules, and based on experience with small molecules, renal excretion can affect PK (higher exposure or lower clearance) in the presence of renal impairment. Except for Adcetris, the impact of severe renal impairment on nine other ADCs has not been studied.

In one study, small molecule MMAE PK was assessed after the administration of Adcetris at a dose of 1.2 mg/kg in subjects with normal renal function (n=8), mild (n=4), moderate (n=3), and severe (n=3) renal impairment.

Results showed that compared to subjects with normal renal function, subjects with mild, moderate, and severe renal impairment had 7%, 22%, and 71% lower AUC for ADC, respectively. The MMAE AUC was comparable between subjects with mild and moderate renal impairment and those with normal renal function. In subjects with severe renal impairment, the MMAE AUC was nearly double that of subjects with normal renal function.

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Hepatic Impairment
Currently, most studies have been conducted on patients with mild hepatic impairment, with no differences found between subjects with normal liver function and mild hepatic impairment. Except for Adcetris, there is no data available for subjects with severe hepatic impairment.

In one study, Adcetris PK was studied at a dose of 1.2 mg/kg in subjects with normal liver function (n=8), mild (n=1), moderate (n=5), and severe (n=10) hepatic impairment.

Results showed decreased AUC for ADC in subjects with hepatic impairment. Compared to subjects with normal liver function, subjects with mild, moderate, and severe hepatic impairment had AUCs of 57%, 65%, and 71%, respectively. The MMAE AUC was 3.5 times higher in subjects with mild hepatic impairment, 2.2 times higher in subjects with moderate hepatic impairment, and 1.77 times higher in subjects with severe hepatic impairment.

Similar to renal impairment, if significant exposure of the payload of the ADC is found in patients with hepatic impairment, it should not be entirely avoided in patients with moderate or severe hepatic impairment, thus depriving patients of the therapeutic benefits of the ADC. Instead, dose adjustment of the ADC should be considered.

External Factors Influencing ADC PK

Drug Interaction Studies
With the exception of TRODELVY, drug interaction studies for ADCs have been conducted quite well and are described in the drug labels. However, drug interaction studies have not been conducted for TRODELVY.

Drug Interaction Studies


From FDA drug labels, it can be seen that at least nine ADCs have undergone immunogenicity studies (excluding Mylotarg). For Mylotarg, assessment reports from the European Medicines Agency indicate that the incidence of antidrug antibodies (ADAs) following treatment with Mylotarg is <1% in four clinical studies. Overall, the incidence of immunogenicity in approved ADCs appears to be relatively low. The impact of antidrug antibodies on PK, efficacy, and safety remains unknown.

There have been no specific assessments of the effects of pregnancy on the PK, efficacy, and safety of ADCs. The drug labels for ADCs provide a general statement: “Due to its mechanism of action, ADCs may cause embryo-fetal harm when administered to pregnant women, as they contain a genotoxic compound and affect active cell division.” Currently, there are no data available regarding the risks associated with the use of ADCs in pregnant women.

There are currently no specific studies on ADCs or their metabolites in breast milk. For some ADCs, there are stipulations that breastfeeding should be avoided for several weeks or months after the last dose of the drug. The FDA also emphasizes that “the importance of the drug to the mother should be considered in deciding whether to discontinue nursing or discontinue the drug.”

It is well known that both intrinsic and extrinsic factors typically have significant impacts on the PK of small molecules, but the effects of these factors on large molecules have not been fully studied. As ADCs are combination products of large molecules (monoclonal antibodies) and small molecules (payloads), it is crucial to study the effects of intrinsic and extrinsic factors on the PK of both molecules.

Efforts have been made to determine the effects of intrinsic and extrinsic factors on ADC PK through population pharmacokinetics. However, it should be recognized that an adequate sample size is required to detect the influence of covariates on PK parameters in population pharmacokinetic analyses. Currently, in many cases such as age, gender, severe hepatic and renal impairment, and drug-drug interaction studies, the sample size is not sufficient to detect the effects of intrinsic and extrinsic factors on the PK of these ADCs. Therefore, more rigorous studies are needed in these areas.

Some ADCs (blenrep, adcetris, padcev, trodelvy, enhertu, and zynlonta) have received FDA accelerated approval, with statements indicating “approval based on tumor response rate and duration of response, accelerating approval for this indication. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.” This may be a risky approach, and only time will tell whether this approach to approving marketed drugs (accelerated approval) is appropriate.

In summary, ADCs are effective drugs for the treatment of cancer. However, the development and approval of ADCs require more rigorous approaches. The impact of intrinsic and extrinsic factors should be carefully evaluated to select the optimal dose for patients or patient populations with specific backgrounds.

1.Effect of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Antibody–Drug Conjugates (ADCs). Antibodies (Basel).2021 Dec; 10(4): 40.


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